1. Field of the Invention
The present invention relates to an apparatus and method for assessing the electrical potential of cells of clinical interest in a living organism using a high-density sensor array system.
2. Background Art
It is well established that transmembrane electrical potentials (sometimes known as electropotentials or biopotentials) in cellular division and in many types of abnormal or cancer cells are markedly different from cells in their normal state. Structural changes in tissue, such as occurs in malignancy, result in changes in electrolyte distribution that can give rise to an abnormal surface charge distribution. Animal and plant cells also have a characteristic profile of ion gradients across the plasma membrane under steady-state conditions.
Malignant cells and normal cells also have different membrane permeabilities which in turn affects the electric potential across the membrane. In 1981, Morris and Hirschowitz published the first clinical study using surface electrical potential measurement to detect human breast cancer. J Bioelectricity, 1982, 1:155-159.
Given the types of ionic species in the extracellular and intracellular fluids, the cell cannot be more negative than −92 mV or more positive that +64 mV. In reality, because the cell membrane has a finite permeability to most ionic species, the actual electrical potential difference at any point in time will lay somewhere within these two figures.
While these static and quasi-static potentials are relatively small and often difficult to measure, physiological processes that give rise to rapidly changing potentials are routinely used. Common examples are changes in nerve cell membrane potentials in the brain measured by electro-encephalogram (EEG) arrays, as well as heart functions measured by electrocardiogram (ECG) devices.
Hirschowitz et al., U.S. Pat. No. 4,328,809, disclosed devices and methods to measure cellular status via analysis of direct current potentials from the surface of the skin. These methods involved the use of individually applied sets, or several sets, of high quality bioelectric sensors. For breast cancer detection, Hirschowitz et al. shows that a test electrode can be placed in each quadrant of a human female breast and that multiple measurements can be taken during a test period with each test electrode and a reference electrode. These multiple measurements are digitized, normalized, and summed to provide an average or mean output signal indicative of a parameter of the living organism under test.
Other electrical potential measuring devices, all utilizing individual electrodes, are shown by U.S. Pat. No. 4,407,300 to Davis, and U.S. Pat. Nos. 4,557,271 and 4,557,273 to Stoller et al. Davis in particular discloses the diagnosis of cancer by measuring the electromotive forces generated between two electrodes applied to a subject.
Measurements of electrical potentials have also been accomplished using geometric arrangements of independent electrodes, with a multiplexing system to switch between electrodes in the arrangement. The aforementioned Hirschowitz et al. patent contemplates the use of a plurality of test electrodes, while U.S. Pat. No. 4,416,288 to Freeman and U.S. Pat. No. 4,486,835, to Bai, disclose other arrangements of measuring electrodes. Using these measurement techniques, U.S. Pat. Nos. 4,955,383 and 5,099,844, Faupel et. al., discloses a method and apparatus using electrical potential differentials between averaged values provided by a plurality of different sensors. This method operates on the basis of maximum differentials between areas of diseased tissue and apparently normal tissue.
However, while clinical results from the continuing human trials for independent sensor set technology demonstrated there were, in fact, bioelectrical changes in the breast indicative of change and cancer, the diagnostic false negative ratios were too high for the technology to be utilized by medical practitioners, independent of how signal analysis was performed.
Efforts have continued to identify a practical alternative diagnostic technology to assess breast lesions, and that could also be applied in the diagnosis of certain other cancers, as well as cellular processes or states, such as inflammation or wound healing.
With regard to breast health, there are only two major methods of detecting suspicious breast tissue. One is a simple physical examination of the breast performed by a woman herself, or by a physician. This type of detection is only relevant for palpable structures. If a suspicious lump is identified, the patient proceeds to biopsy.
The other method is imaging studies, known as mammography. If a mammogram detects a suspicious area, the patient is then sent for follow-up procedures, such as biopsy. However, mammograms are unable to detect rapidly dividing cancer cells prior to their formation into a tumor of a certain density. Additionally, they are painful to women and fail to adequately include portions of the breast because of the compression technique applied.
The American College of Radiology (ACR) employs the standardized Breast Imaging Reporting and Data System (BIRADS) for reporting mammography results. This diagnostic system remains very subjective, however, with definitions such as “probably benign” and “suspicious abnormality”, leaving a lot of room for interpretation and often requiring additional tests. In 90% of suspicious cases, even after diagnostic mammography, a patient will still have to undergo breast biopsy to obtain a specimen for histological diagnosis.
Although surgical biopsy has historically been accepted as the gold standard for histological diagnosis, biopsies have an error rates from 0.2% to as high as 20% [Medicare/Medicaid SCHIP, Medicare Coverage Policy; Breast Biopsy (#CAG-00040) Decision Memorandum, Dec. 7, 1999]. This means that even after a biopsy, a woman may not have a definitive analysis of her condition, leading to either unnecessary mastectomy or misdiagnosed cancer. Other serious drawbacks include the facts that the technique can be disfiguring, time consuming, and expensive.
There are over one million breast biopsies performed in the United States each year. According to multiple clinical studies, American Cancer Society and Medicare Statistics, the biopsy report proves to be benign for 70-80% of all breast biopsies. Therefore, approximately 750 out 1000 women undergo breast biopsies unnecessarily. Exclusion of even 50% of patients from biopsy processes would translate into significant savings, with funds otherwise tied up in biopsy costs used for additional screening of the population and ultimately in the saving of lives.